Alzheimer's disease (AD) is an age-related neurodegenerative disorder associated with severe memory impairments for which, currently, there is no cure. Although the role of beta-amyloid (A[unreadable]) in the disease is strongly supported by genetic evidence, the mechanism between A[unreadable] and neurodegeneration/memory impairments is far from clear. In combating AD, it is imperative that we expand our approach beyond the current focus upon amyloid pathology. Research into novel therapeutic approaches to combat the symptoms of AD has revealed beneficial effects of increased chromatin remodeling and gene expression. We have shown that small molecule inhibitors of histone deacetylases (HDACs) restore learning ability in the CK-p25 mouse model of AD even after severe neuronal loss has occurred. The class I histone deacetylase, HDAC2, has been shown to participate in the regulation of hippocampal-dependent learning and memory. HDAC2 binds to the regulatory elements of genes implicated in synapse formation and synaptic plasticity, and is upregulated in both the CK-p25 and the 5XFAD mouse models of AD. These findings have led to the idea that, during neurodegeneration, an altered epigenetic landscape, mediated by HDAC2 up-regulation, may repress the expression of gene products necessary for maintaining synaptic plasticity and memory functions. Thus, inhibition of HDAC2, even after the onset of neurodegeneration, can improve the function of surviving neurons. In the current application, we will test the hypothesis that a novel disease mechanism, involving HDAC2 mediated alteration of the epigenetic landscape, underlies the cognitive impairment and synaptic dysfunction of Alzheimer's disease. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is an age-related neurodegenerative disorder associated with severe memory impairments for which, currently, there is no cure. We have shown that small molecule inhibitors of histone deacetylases (HDACs) restore learning ability in the CK-p25 mouse model of AD even after severe neuronal loss has occurred. The current application will test the hypothesis that a novel disease mechanism, involving epigenetics, underlies the cognitive impairment and synaptic dysfunction of Alzheimer's disease.